Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons

The efficiency of first-generation adenoviral vectors as gene delivery tools is often limited by the short duration of transgene expression, which can be related to immune responses and to toxic effects of viral proteins. In addition, readministration is usually ineffective unless the animals are immunocompromised or a different adenovirus serotype is used. Recently, adenoviral vectors devoid of all viral coding sequences (helper-dependent or gutless vectors) have been developed to avoid expression of viral proteins. In mice, liver-directed gene transfer with AdSTK109, a helper-dependent adenoviral (Ad) vector containing the human α1-antitrypsin (hAAT) gene, resulted in sustained expression for longer than 10 months with negligible toxicity to the liver. In the present report, we have examined the duration of expression of AdSTK109 in the liver of baboons and compared it to first- generation vectors expressing hAAT. Transgene expression was limited to approximately 3-5 months with the first-generation vectors. In contrast, administration of AdSTK109 resulted in transgene expression for longer than a year in two of three baboons. We have also investigated the feasibility of circumventing the humoral response to the virus by sequential administration of vectors of different serotypes. We found that the ineffectiveness of readministration due to the humoral response to an Ad5 first-generation vector was overcome by use of an Ad2-based vector expressing hAAT. These data suggest that long-term expression of transgenes should be possible by combining the reduced immunogenicity and toxicity of helper-dependent vectors with sequential delivery of vectors of different serotypes

Global-scale hydrological response to future glacier mass loss

Worldwide glacier retreat and associated future runoff changes raise major concerns over the sustainability of global water resources1,2,3,4, but global-scale assessments of glacier decline and the resulting hydrological consequences are scarce5,6. Here we compute global glacier runoff changes for 56 large-scale glacierized drainage basins to 2100 and analyse the glacial impact on streamflow. In roughly half of the investigated basins, the modelled annual glacier runoff continues to rise until a maximum (‘peak water’) is reached, beyond which runoff steadily declines. In the remaining basins, this tipping point has already been passed. Peak water occurs later in basins with larger glaciers and higher ice-cover fractions. Typically, future glacier runoff increases in early summer but decreases in late summer. Although most of the 56 basins have less than 2% ice coverage, by 2100 one-third of them might experience runoff decreases greater than 10% due to glacier mass loss in at least one month of the melt season, with the largest reductions in central Asia and the Andes. We conclude that, even in large-scale basins with minimal ice-cover fraction, the downstream hydrological effects of continued glacier wastage can be substantial, but the magnitudes vary greatly among basins and throughout the melt season

A Quantitative Trait Locus Influencing Activin-to-Estrogen Ratio in Pedigreed Baboons Maps to a Region Homologous to Human Chromosome 19

Activin is a multifunctional hormone playing a major role in the regulation of reproduction and growth and development. We performed a genomewide scan using multipoint linkage analysis implemented in a general pedigree-based variance component approach to identify genes with measurable effects on variation in the activin-to-estrogen ratio in baboons. A microsatellite polymorphism, D19S714, which maps to human chromosome 19p13.2, showed marginal evidence of linkage with a lod (log10 of the odds in favor of genetic linkage) score of 1.95 (0.014). This region contains several potential candidate genes including PKA (protein kinase, cAMP-dependent, catalytic α) and the gene pair JUN-B and JUN-D. This is the first evidence of a quantitative trait locus with a significant effect on the activin-to-estrogen ratio

Transcriptional landscape of the prenatal human brain.

The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development